PB1917: PROGNOSTIC AND PREDICTIVE SIGNIFICANCE OF ELEMENTS OF THE ADAPTIVE IMMUNITY IN THE MICROENVIRONMENT OF MYELODYSPLASTIC SYNDROMES TREATED WITH 5-AZACITIDINE
Authors: Z. Tsakiraki, S. Papageorgiou, A. Spathis, A. Pouliakis, A. Bouchla, T. Thomopoulos, I. G. Panayiotides, V. Pappa, P. Foukas
Journal: HemaSphere (2022)

Background: Myelodysplastic syndromes (MDS) are an heterogenous group of clonal hematopoietic neoplasms. Aims: Our objectives were to investigate the immune micro-environment of bone marrow (BM) trephine biopsies from patients with high risk MDS and whether elements of the adaptive immunity predict response to 5-Azacitidine (5-AZA) treatment. Methods: The study population consisted of 65 patients with intermediate and high-risk MDS (n=57) according to IPSS-R and oligoblastic acute leukemias (n=8), treated with 5-AZA. Sections from BM trephine specimens before (n=65) and during treatment (n=28) (interval: 6-12 months), were immunostained for CD3, CD8, CD20, CD138 and Foxp3, for T cells, cytotoxic T cells, B cells, plasma cells and regulatory T cells, respectively. The slides were digitally scanned and the number of positive cells was counted in five areas with the highest density of CD8(+) cells, a well validated antineoplastic population. Since BM cellularity varied between specimens, all cell counts were normalised to 1mm2 of tissue area after removing fat and empty spaces. CD4(+) T helper cells were calculated indirectly subtracting cytotoxic from total T cells. The study also included a control group consisting of 20 normal BM trephine biopsies. Results: - Patients presented with lower number of FoxP3(+) cells per mm2, FoxP3/CD3 ratio and FoxP3/CD8 ratio (p<0.001, Mann-Whitney) compared to controls. - Patients that had a complete or partial response had higher CD3(+) and CD4(+) T cell density prior treatment (887 vs. 732, p=0.041 and 376 vs 262 p-0.034, Mann-Whitney) and had decreased both populations after treatment (-251 vs. +153 p=0.001 and -148 vs. +58.4, p=0.038, Mann-Whitney). - In MDS cases before treatment, lower CD3(+) T, CD4(+) Th and CD8(+) Tc cell densities, FoxP3/CD3 and FoxP3/CD8 ratios were significantly correlated with decreased overall survival (OS) (p=0.049, 0.045, 0.043, 0.008 and 0.049, respectively). During treatment with 5-AZA, increased levels of CD3(+) T (p=0.012) and CD20(+) B (p=0.012) cells and decreased levels of Foxp3(+) Tregs (p=0.043), FoxP3/CD3 and FoxP3/CD8 ratios (p=0.043, Cox) were significantly correlated with decreased OS. - In the entire population no significant changes were observed when comparing prior and during therapy cell densities. However, decrease in OS was found when patients retained or increased CD3(+) or CD4(+) cell densities in matched, before and during treatment, samples (p=0.026 and p=0.002, Cox). - Moreover, higher plasma cell densities before and during treatment were found in patients that transformed to AML earlier (17.9 months vs. 47.5 months, p=0.001 and 22.8 months vs. 50.8 months, p=0.022, Kaplan Meyer). Summary/Conclusion: Our results indicate that the density of cells of adaptive immunity in the bone marrow specimens may significantly contribute to outcome (overall survival and time to transformation to AML) of high-risk MDS patients and alter response to treatment with 5-AZA.